We hypothesize that the host-pathogen interface that mediate the innate immune response to HIV infection is comprised of three fundamental components: (i) recognition and induction of signaling by innate immune receptors, (ii) cellular antiviral responses, and (iii) viral evasion of innate restriction mechanisms. Aspects of these viral-host circuits are beginning to be uncovered, and include innate immune recognition of HIV RNA by the TLR7 pattern recognition receptor, restriction of HIV replication by interferon inducible HIV restriction factors Apobec3G and BST2, and inactivation of the latter two molecules by the HIV-encoded proteins Vif and Vpu, respectively. However, comprehensive insight towards the molecular circuitries that underiies these host and viral responses has yet to be established. Towards this end, we propose to employ a systemsbased strategy to map signaling networks and host-pathogen interactions that form the basis of innate immune responses to HIV infection. This approach will leverage existing functional genomics and proteomics datasets, and also will rely on novel systems-based studies, including RNAi and protein interaction analysis, to comprehensively delineate these innate and host-pathogen networks. For this purpose, we have assembled a team of two co-PIs with significant experience in the field of systems biology. Dr. Chanda has over 10 years experience in functional genomics and genetic analysis in mammalian cells, and Dr. Krogan brings over 10 years of experience in the areas of large-scale proteomic and network analysis. These studies are expected to provide global molecular insight into cellular and viral processes that regulate eariy immune responses to HIV infection.